GWAS: Clostridium Difficile
Clostridium difficile is a Gram-positive bacilli and obligate anaerobe that causes gastrointestinal diseases including diarrhea, pseudomembranous colitis, and toxic megacolon (Carroll and Bartlett 2011) (Sehulster and Chinn 2003). Spores increase the survival rate and reproduction of C. Difficile because it is highly resistant to temperature, UV radiation, most disinfectants and antibiotics(Rupnik et al. 2009). C difficile produces endospores under environmental stress. These spores lie dormant for long periods of time until they sense that environment conditions are more suitable to transform into a vegetative cell (Setlow 2007). The cells can reproduce in abundance and fluster the normal gastrointestinal flora (Maroo and Lamont 2006). Due to the nature of spores, complications have been rising in nosocomial infections associated with a high rate of mortality and financial conflicts in the healthcare system (Khanna et al. 2012 and Ghantoji et al. 2010). Since sporulation has been extensively studied in Bacillus subtilis, some aspects can also be applied to Clostridium spp. because it possesses the same regulatory proteins that control spore coat gene expression (Henriques et al. 2007), including sporulation sigma factors σF, σE, σG, σK and the master transcriptional regulator, Spo0A. Except, only 25% of the spore coat proteins are actually conserved in C. Difficile. Based on previous studies in Bacillus subtilis and other Clostridium spp., the sigma factors σF, σE, σG, and σK are predicted to control the transcription of genes required for sporulation (Fimlaid et al. 2013) During sporulation in B. subtilis, in certain stages the sigma factors determine the expression of genes that in turn leads to morphological changes in the cell. The morphology formation of a spore begins with the polar septum creating two compartments known as the the mother cell and the fore-spore. In order to guide the assembly of the spore until lysis of the mother cell which denotes complete maturation, the fore-spore is engulfed by the mother cell. The signma factors promote transcription of certain genes that are needed in sporulation. Research Fimlaid's research generated the first genome-wide transcriptional analysis of genes induced by specific sporulation sigma factors in the Clostridia and highlights the diverse mechanisms used to regulate sporulation sigma factor activity. This research focused on figuring out which genes were regulated by the sporulation-specific sigma factors, σF, σE, σG, and σK. By using TargeTron gene knockout system to disrupt the genes encoding certain proteins. The goal of this study was to characterize new proteins needed for sporulation in order to determine their function in spore development, which is responsible for the high rates of disease recurrence that can lead to life-threatening complications. Each strain of C. diff has a different phenotype and by introducing mutations into certain ones, researchers can analyze the consequences and see which factors are more important than others. Also, this research will contribute to future research by identifying certain genes that are highly regulated. Highly regulated genes are deemed important during sporulation because they encode for certain proteins that may lead to the discovery of biomarkers for C. difficile spores that could potentially lead to vaccine development. By generating the first genome-wide transcriptional analysis of genes, genes that are highly regulated by the known factors can now be characterized. Determining their function in spore development, which is responsible for the high rates of disease recurrence that can lead to life-threatening complications will help with future research. New research can look into sporulation proteins that may lead to the discovery of biomarkers for C. difficile spores that could potentially lead to vaccine development. This would come a long way in helping future research apply the knowledge to clinical applications and therapeutic methods. References #Fimlaid et al. (2013) Global Analysis of the Sporulation Pathway of Clostridium difficile. PLoS Genet; 1003660 #Carroll K, Bartlett J (2011). Biology of Clostridium difficile: implications for epidemiology and diagnosis. Ann Rev Microbiol 65: 501–521. #Sehulster L, Chinn RYW (2003). Guidelines for environmental infection control in healthcare facilities. CDC, MMW; 52(RR10);1–42. #Rupnik M, Wilcox M, Gerding D (2009). Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 7: 526–536. #Setlow, P. (2007), I will survive: DNA protection in bacterial spores, Trends in Microbiology. 15(4);172-180. #Maroo S, Lamont J (2006) Recurrent Clostridium difficile. Gastroenterology 130: 1311-1316. #Khanna et al. (2012) The epidemiology of community-acquired Clostridium difficile infection: a population-based study. Am J Gastroenterol 107: 89–95 #Ghantoji et al. (2010) Economic healthcare costs of Clostridium difficile infection: a systematic review. J Hosp Infect 74: 309–318.